Difficulties with intellectual functioning, particularly memory functions, are common and source of long-term disability after Traumatic Brain Injury (TBI). However, there is very little information about pharmacologic (i.e., medication) treatments targeting these deficits. There are growing data showing brain abnormalities in acetylcholine, the chemical system that manages memory, in TBI. These findings provide the rationale for the use of cholinesterase inhibitors, medications that modulate this system, in TBI patients. As the prevalence of TBI among Veterans of recent military conflicts increases, becoming a "signature injury" of the Iraq and Afghanistan conflicts, it is of utmost importance to the Veterans Health Administration to collect scientific data on the efficacy of pharmacological treatments for intellectual difficulties in TBI patients. This study will evaluate the effects of the cholinesterase inhibitor rivastigmine transdermal patch in Veterans with TBI and posttraumatic memory problems. Results will provide much needed data that will help treat Veterans with TBI.

Efficacy will be determined by comparing the proportion of patients in each treatment group who are classified as responders at week 12. Treatment response is defined as a minimum 5-word improvement across alternate test forms from baseline to 12-weeks as measured on the HVLT-R total learning for Trials 1-3

Traumatic brain injury (TBI) represents one of the most significant health risks related to military duty; rapidly becoming the "signature injury" of the Iraq and Afghanistan conflicts. TBI patients often experience multiple cognitive problems, with disturbances in memory, attention, and executive functions among the most common. Disturbances in memory as well as attention are particularly problematic, as disruption of these relatively basic cognitive functions may exacerbate or cause additional disturbances in executive function, communication and other more complex cognitive domains. These cognitive deficits, especially when memory is affected, significantly impact day-to-day functioning and are the source of lingering disability and distress to the affected individuals. However, despite advances made in TBI care, treatment of cognitive deficits in TBI lag behind, forcing clinicians to provide treatment without the guidance of evidence-based scientific data. This proposal aims to begin the process of providing clinicians with evidence-based guidelines for pharmacological management of Veterans with TBI suffering from persistent cognitive deficits following their injuries. This aim will be accomplished by conducting a clinical trial in Veterans suffering from moderate to severe posttraumatic memory impairment following TBI. Specifically, this proposal will evaluate the efficacy and safety of rivastigmine transdermal patch, an intermediate-acting cholinesterase inhibitor, in this population.

We hypothesize that rivastigmine transdermal patch will be more effective than, and equally safe as, placebo in the treatment of moderate to severe posttraumatic memory impairment in Veterans with TBI when tested in a randomized, multi-site, parallel design, placebo-controlled trial, at a 12-week endpoint. The exploratory hypothesis states that compared to placebo, rivastigmine patch will be more effective and equally safe in the treatment of patients who will continue in a randomized, placebo-controlled phase for a total of 26 weeks. To test these hypotheses we will evaluate the effect and the safety of rivastigmine 9.5 mg/24 hours (10cm2) transdermal patch in 138 Veterans who meet or exceed the criteria for closed, non-penetrating, mild TBI and who present at baseline with moderate to severe memory impairment. Memory impairment will be defined as a Total Recall index (Trials 1-3) of the Hopkins Verbal Learning Test-Revised (HVLT-R) that is at least 25% lower than the intelligence-adjusted expected score, as assessed by the WAIS-IV Information and Vocabulary subtests. The study consists of a screening period, one-week single-blind, placebo run-in phase, and a 12-week double-blind acute treatment phase (Phase I). Subjects will be randomized 1:1 to rivastigmine transdermal patch 9.5mg/24 hours (10cm2) or matching placebo. During Phase I, there will be an initial 4-week titration period followed by an 8-week continuation phase. Following the 12-week acute treatment phase, randomized patients will continue in the double-blind phase (Phase II) for additional 14 weeks or until study treatment period ends. Efficacy will be determined by comparing the proportion of patients in each treatment group who are classified as responders at week 12. Secondary measure of functional capacity assessing the impact of memory improvement on real-world functioning, other measures of cognitive domains affected in TBI, namely attention, working and episodic memory and executive functions, as well as measures of mood and quality of life will be examined. Study findings will contribute to the body of evidence needed to establish standards of care for Veterans with posttraumatic memory impairment and other cognitive deficits.

Eligibility

Ages Eligible for Study:

19 Years to 65 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Be a male or a female of any race

Be outpatient Veterans residing in the community

Be 19-65 years old at the time of inclusion

Female patients of childbearing potential must have a negative pregnancy test at baseline and must practice an acceptable method of birth control during the trial

Satisfy the following diagnostic criteria:

A history of previous head trauma(s) at least 12 months prior to study enrollment as determined by TBI diagnostic assessment

Meet or exceed the modified ACRM criteria for Mild TBI as determined by TBI diagnostic assessment

Have a deficit in the area of verbal memory

Have subjective memory impairment that was reported to be present from the time of injury or shortly thereafter to be associated with brain injury

Satisfy the DSM-IV-TR criteria for cognitive disorder not otherwise specified, dementia due to TBI, or amnestic disorder due to TBI

Demonstrate willingness to accept randomization

Provide written informed consent to participate in the study

Exclusion Criteria:

Have a medical condition that can interfere with the diagnostic process and the assessment of clinical and mental status, or possibly endanger their health. Such conditions include, but are not limited to endocrinological, neurological (including epilepsia), cardiovascular (including clinically significant bradyarrhythmia, resting heart rate <50 without a or treating physician's approval),pulmonary, hematologic, hepatis, and renal conditions, and significant laboratory abnormalities as determined by Study Chair.

Have a current diagnosis of any primary neurodegenerative disorder, including Huntington's disease, Parkinson's disease, or DSM-IV-TR dementia (other than Dementia Due to Head Trauma)

Have suicidal ideation or have been judged to be a significant suicide risk

Have a history of DSM-IV-TR substance (drug and/or alcohol) dependence disorder within the last 5 years or a history of a substance abuse disorder within the past 6 months

Have current PTSD symptoms that can bias or interfere with cognitive and clinical assessments as determined by study site PI.

Have demonstrated suboptimal effort on cognitive testing as defined by:

TOMM raw score below 45 on either Trial 2 or the Retention Trial, or

MSVT score of <=85% on any one of the Immediate Recall, Delayed Recall, or Consistency indices.

Have demonstrated a lack of tolerability to rivastigmine treatment in the past or severe reactions to other cholinesterase inhibitors as determined by the site investigator

Be taking medications that significantly affect cognitive functioning in TBI population and/or may enhance the beneficial/adverse/toxic effect of rivastigmine or vice versa. These compounds include, but are not limited to, centrally-acting anticholinergic drugs (e.g. atropine), other cholinesterase inhibitors (e.g. donepezil, galantamine) and agents that augment cerebral catecholaminergic function (e.g) psychostimulants, amantadine, memantine, selegiline, levodopa, etc). Treatment of non-exclusionary comorbid psychiatric symptoms with compounds that include, but are not limited to, antidepressants, anxiolytics, sedative-hypnotics, anticonvulsants, and atypical antipsychotics will be permitted provided that: 1) the site investigator, based on review of medical history, records and current medications and in consultation with the Study Chair, concludes that the agent(s) are neither cause(s) of nor significant contributor(s) to the potential subject's memory impairment; 2) the dose of the agent(s) has been stable for the 3 months preceding study participation; and 3) the dose of the agent(s) remains stable, where clinically feasible, throughout the study. For medications prescribed for non-exclusionary conditions on a PRN basis, particularly when those medications include benzodiazepines, sympthomimetics, antitussive agents or potentially sedating analgesics- every use will be documented by the subject and will not be taken within 24 hours of performing study-related cognitive testing (Appendix A: Exclusionary Medications).

Have been exposed to other cholinesterase inhibitors in the 30 days prior to randomization

Have a history of penetrating brain injury, cerebrovascular disease, cerebral neoplasm, major brain surgery, or multiple sclerosis

Have a significant visual or auditory deficit that may interfere with ability to complete study assessments

Have a limited ability to speak and read English

Be participating in another clinical trial with active intervention

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01670526